Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that is manifested clinically by an elevation in hepatic triglycerides, inflammation, and fibrosis. The pathogenesis of NASH remains incompletely understood. Sirtuin 6 (Sirt6), an NAD-dependent deacetylase, has been implicated in the fatty liver disease; however, the underlying molecular mechanisms in the NASH pathogenesis are elusive. The aims of this study were to elucidate the role of hepatic Sirt6 in NASH. Wild-type (WT), liver-specific Sirt6 knockout (KO), hepatic stellate cell (HSC)-specific Sirt6 knockout (HSC-KO), and Sirt6 transgenic (Tg) mice were subjected to a Western diet for 4 weeks. Hepatic phenotypes were characterized and underlying mechanisms were investigated. Remarkably, both the liver-KO and HSC-KO mice developed much worse NASH than the WT mice did whereas the Tg mice were protected from the diet-induced NASH. Our cell signaling analysis revealed that Sirt6 negatively regulates the TGFβ-Smad3 pathway. Biochemical analysis showed a physical interaction between Sirt6 and Smad3 in hepatic stellate cells. Moreover, our molecular data further demonstrated that Sirt6 deacetylates Smad3 at key lysine residues K333 and K378 and attenuates its transcriptional activity induced by TGFβ in the hepatic stellate cells. Our data suggest that SIRT6 plays a critical role in the protection against the NASH development and it may serve as a potential therapeutic target for NASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder with limited treatment options. This review explores the role of post-translational modifications (PTMs) in MASLD pathogenesis, highlighting their potential as therapeutic targets. We discuss the impact of PTMs, including their phosphorylation, ubiquitylation, acetylation, and glycosylation, on key proteins involved in MASLD, drawing on studies that use both human subjects and animal models. These modifications influence various cellular processes, such as lipid metabolism, inflammation, and fibrosis, contributing to disease progression. Understanding the intricate PTM network in MASLD offers the potential for developing novel therapeutic strategies that target specific PTMs to modulate protein function and alleviate disease pathology. Further research is needed to fully elucidate the complexity of PTMs in MASLD and translate these findings into effective clinical applications.

IMB1603, a spiro-benzothiazone compound discovered by our lab, displayed potent anti-MTB activity in vitro and in vivo. In this study, we reported a series of new BTZs containing the hexahydropyrrolo[3,4-c]pyrrol moiety based on the structure of IMB1603. Among them, BTZs 11 and 24 displayed potent anti-MTB (MIC < 0.035 μM) and MDR-MTB (MIC, 0.053–0.102 μM) activity, good solubility (1.82–1.85 μg mL⁻¹), and low cytotoxicity (CC₅₀ > 200 μM), suggesting BTZs 11 and 24 may serve as promising candidates for further study. The molecular docking study of 11 toward DprE was also investigated, and revealed that 11 mimicked the binding pattern of PBTZ169 in the active site of DprE1.